Microcirculatory Effects of Abciximab and Eptifibatide: A Critical Appraisal<br />

The coronary microcirculation is critically important in the maintenance of myocardial nutritive blood flow. Even in situations where measures of epicardial blood flow appear normal, abnormalities in microcirculatory integrity secondary to microvascular occlusion may precipitate myocardial infarction and regional myocardial dysfunction. Atherothrombotic embolization of the distal microcirculation may occur spontaneously following plaque rupture during acute coronary syndromes or may occur secondary to percutaneous coronary intervention (PCI) induced plaque disruption. The debris produced by coronary stent deployment is composed of atherosclerotic plaque components (fibrin, necrotic core, foam cells, cholesterol clefts) as well as organized thrombus of variable degree. In addition, platelet as well as white cell-platelet aggregates which form at the site of endoluminal vessel injury or on the surface of the metallic stent prosthesis contribute to the process of embolization and distal microvascular occlusion. As the pathogenesis of microvascular obstruction is multi-factorial, both pharmacologic and mechanical strategies for embolic protection have been devised. All three currently available platelet glycoprotein (GP) IIb/IIIa receptor blockers have been demonstrated to reduce the incidence of periprocedural myocardial infarction associated with PCI as reflected by CK-MB elevation. The mechanism for this benefit is attributed in large part to a reduction in platelet aggregates and platelet embolization and to a lesser extent, preservation of side branch integrity following coronary stent deployment. The degree of “protection” provided by GP IIb/IIIa receptor blockade is influenced by the pathophysiologic substrate and is not demonstrable following PCI of saphenous vein graft stenoses, possibly reflecting the burden of atherothrombotic debris produced.1,2 Indeed, atherosclerotic plaque disgorgement and plaque volume reduction following coronary stent deployment as demonstrated by intravascular ultrasound evaluation, has been directly correlated with periprocedural CK-MB elevation, particularly in patients who present with unstable angina pectoris.3 Thus, it is no surprise that platelet GP IIb/IIIa blockade provides variable and incomplete protection against microvascular occlusion considering the multiple diverse factors which contribute to this phenomenon. Various techniques to evaluate microcirculatory integrity have been proposed and validated in specific patient subsets. Most notably, these have included Doppler flow wire assessment of coronary flow reserve, contrast echocardiography, TIMI myocardial perfusion or “blush” grade (TMBG) and the magnitude of electrocardiographic ST segment resolution (> 70%) following mechanical or pharmacologic reperfusion for ST segment elevation acute myocardial infarction (MI). In the current issue of the Journal, Stoupakis et al.4 purport to demonstrate similarity in microvascular preservation following elective coronary stent deployment in a consecutive series of patients undergoing PCI for stable angina, unstable angina or See Stoupakis et al. on pages 476–480 non-ST segment elevation MI, who received adjunctive periprocedural pharmacotherapy with either abciximab or eptifibatide. On critical review, the hypothesis of this study (“that there would be no difference in preservation of microcirculatory perfusion as assessed by TMBG, between abciximab or eptifibatide”) remains unproven due to flaws in methodology and study design. The premise of this investigation is to provide rational justification in support of clinical practice at the investigator’s institution. As stated by the authors, “Based on data from the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial, our institution decided on a cost-effective shift towards the use of eptifibatide in all patients presenting with stable or unstable angina.” Of note, patients who presented with an acute coronary syndrome were by protocol definition to have been excluded from participation in the ESPRIT trial.5 To what “cost-efficacy” benchmark do they refer? In the absence of any survival advantage (cost per life year gained) in favor of eptifibatide, was “cost per myocardial infarction prevented” or merely procurement cost the objective? The authors correctly state “there is no study comparing the efficacy of abciximab to eptifibatide on perfusion in the myocardial microcirculation following PCI in either stable or acute coronary syndrome”. Unfortunately, for multiple reasons, their work does not alter that conclusion. First, although TMBG has been demonstrated to provide independent risk stratification among patients with normal TIMI grade 3 epicardial blood flow following reperfusion of ST segment elevation MI, scant validation exists for this technique as a correlate or surrogate endpoint following elective PCI in stable or unstable angina pectoris or for non-ST segment elevation MI. Thus, the authors statement, “it is assumed appropriate to use this technique to assess myocardial perfusion in patients presenting with stable or unstable angina based on its validation in patients presenting with ST elevation AMI” is conjecture. Indeed, not a single reference supporting the use of TMBG in patients without ST segment elevation MI is provided. Furthermore, even following PCI for ST segment elevation MI, the implicit assumption that TMBG correlates with enhanced regional myocardial function and improved clinical outcomes is dependent on successful preservation of epicardial blood flow. For example, in the Integrilin in Acute Myocardial Infarction (INAMI) trial which evaluated adjunctive eptifibatide therapy during PCI for ST elevation MI, despite apparent salutary effects of eptifibatide on the microcirculation (normal TMBG grade 3 in 87% of patients) subacute stent thrombosis was observed in 9% of patients,6 much higher than previously observed in the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC)7 randomized trial of abciximab adjunctive pharmacotherapy during PCI for AMI. Second, the present study represents a retrospective, non-randomized analysis of consecutive patients. Although the authors state “baseline characteristics between the two groups (eptifibatide and abciximab) were balanced” in fact, no attempt at propensity scoring to adjust for selection bias was employed and important differences between pharmacologic treatment groups could be present but not detected secondary to the small number of patients analyzed. We are told that “50 patients per treatment arm were required to provide 80% power to detect differences of 25–30% in the proportion of TMBG 3 between the two groups in a two-sided test at an alpha level of 0.05”. Power calculations are usually based on an assumed endpoint occurrence within a relatively homogenous population. A single power calculation would not be appropriate for a population of widely divergent risk for adverse events (stable angina vs. unstable angina/non-ST elevation MI). Normal TMBG grade 3 was observed in 67% of abciximab vs. 58% of eptifibatide-treated patients. More importantly, we are not told the power calculations for detecting a difference in TMBG 0-1 or the beta error level for missing important differences in a 100 patient non-randomized comparison. For example, TMBG 0-1, which has been most closely correlated with troponin elevation following PCI in non-ST elevation acute coronary syndromes8 and with reduced cardiovascular event free survival following PCI for MI9 was observed in 6% of eptifibatide vs. 2% of abciximab-treated patients. This three-fold difference in a powerful correlate of adverse clinical outcomes could be statistically significant in a larger patient cohort. Indeed, absence of an observed apparent difference in this study should not be inferred to mean “no difference”. Third, the reliability of the endpoint measured in this study may be in question. We are told that “angiograms were evaluated for TMBG by two experienced investigators who were blinded to all data apart from the coronary angiograms”. What “experience” in evaluating TMBG prior to this study is not disclosed. What was the inter- and intra-observer variability in TMBG scoring? If there is an 83% agreement concurrence between observers and the 17% difference was by “one grade”, this could materially influence the observed differences in TMBG 0-1 grade between pharmacologic treatment groups. How were differences in “one-grade” between expert investigators resolved? In addition, what measures were taken to assure maintenance of a blinded analysis? Did the investigators who determined TMBG also perform the PCI procedures? If so, what proportion of procedures? Maintenance of a blind would be of greatest concern regarding the most recently performed procedures (eptifibatide), as a change in TMBG 0-1 grade status for even 2 patients could significantly alter the observations made. Furthermore, it is surprising that in a retrospective analysis performed without established standardized prospective protocol-driven angiographic technique, evidently no films were discarded as technically inadequate. This is remarkable in view of the retrospectively applied inclusion criteria for requiring “cine filming must exceed 3 cardiac cycles in the washout phase to assess washout of the myocardial blush”. Prolonged cine angiography must be standard practice following elective PCI at the authors’ institution. Lastly, the only “significant” finding of this study — a lower TMBG score following PCI in patients with prior PCI or surgical coronary revascularization is perplexing. Evidently, prior stenting occurred in 33% and prior coronary surgical revascularization of the target vessel was present in 71% of these patients. The authors hypothesis that “lower TMBG is secondary to irreversible microvascular dysfunction resulting from distal microembolization during the previous revascularization procedure” is questionable at best. Are we to believe that successful epicardial revascularization is frequently (invariably) associated with permanent microvascular impairment and yet infrequently associated with periprocedural myocardial necrosis? Unfortunately, neither baseline or post procedural left ventricular regional wall motion nor preprocedural TMBG scores, (both of which could be helpful in deciphering the effects of prior revascularization) are provided. Indeed, in the present study, troponin I levels were obtained on admission and every 8 hours until catheterization. The pre-PCI troponins are then correlated with post-PCI TMBG. This is contrary to the precedent correlation of post-PCI troponin elevation with TMBG8 and does not lend supportive evidence for the author’s theory of universal embolic injury post-PCI (post-procedural troponins would have been enlightening). The authors (and readers) would have been better served to have prospectively compared TMBG with (vs. without) adjunctive eptifibatide alone or in patients randomly assigned to receive either eptifibatide or abciximab than by the current nonrandomized retrospective analysis. No assumptions regarding similarities in microvascular preservation between abciximab and eptifibatide should be made. The marked differences in pharmacokinetics, pharmacodynamics and receptor affinity between these two agents have been described.10,11 The demonstrated affinity of abciximab for the avb3 (vitronectin) and CD11b/18 (MAC1) receptors may affect white cell adhesion,12 white cell-platelet aggregate formation,13 leukocyte transmigration,14 as well as monocyte-macrophage infiltration,15 all of which may influence microvascular integrity. Small molecule inhibitors of the platelet GP IIb/IIIa receptor may not alter infarct zone white blood cell content as reflected by myeloperoxidase activity (compared with placebo) following coronary reperfusion of MI in the animal model.16 Carefully conducted investigations have previously documented the benefit of abciximab (not eptifibatide) on microcirculatory function in acute MI and unstable angina pectoris.17–19 What is needed at present is validation for correlation of TMBG with clinical outcomes in patients without ST elevation MI and a systematic, prospective randomized evaluation of the microvascular effects of adjunctive pharmacotherapy with eptifibatide and abciximab. These data are not provided by the current investigation.

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